Friday, August 1, 2008

Auguste Forel & Brain Plasticity

Today the Swiss celebrate the founding of their confederation. The Swiss Confederation was conceived in a tax revolt more than 700 years ago, making Switzerland today's oldest post-classical European democratic republic governed on federal principles. I take this occasion to commemorate some of the achievements of the Switzerland's most eminent physician neuroscientist Auguste-Henri Forel. A summary of his contributions to neuroscience can be found at

Auguste-Henri Forel was born on September 1, 1848, in the wine country on the banks of Lake Geneva outside Lausanne. He attended secondary schools in Lausanne, but turned to the University of Zürich, when the time came to enroll for medical school. Young Forel loathed the decision. The move to Zürich entailed crossing the language barrier. It meant studying and being taught in German and living with people who speak a German dialect that is difficult to acquire. Even today, the francophonic region of Switzerland boasts only two full-track medical schools. Competition for posts is stiff and the pressure to conform is high. Auguste Forel apparently was made to realize early that he would not fit in. Besides, German universities were famous for the great scientific discoveries of the time, appealing strongly to the young inquisitive mind.

The sacrifice of home paid off for Forel. In the Teutonic sphere, he enjoyed an outstanding career as a psychiatrist and neuro-anatomist, working with a number of highly-respected researchers of the 19th century. He helped to establish a theory of the neuron still valid today. His was the first theory that recognized the role of the nerve cells as independent fundamental building blocks of the networks that process information in the brain. He was appointed director of one of the earliest psychiatric research hospitals in continental Europe. At this institution, he examined the effects of alcoholism on the brain. He was one of the first psychiatrists to study human sexuality with scientific methods. In his book on this subject, he did not shy away from discussing homosexuality and other cultural taboos of his time. He wrote legal opinions on the implications of mental illness for criminal code. He understood that every act of our mind had a molecular mechanism in the brain. An account of his writings on the human condition and the ensuing controversies can be found at Humbolt University's Archive for Sexology.

In addition to research on the human brain and mind, Forel developed a passion for the behavior of social insects at an early age and became a reputed specialist in ant taxonomy. After retiring from his duties as hospital director, he returned to the vineyards of francophonic Switzerland. The village where he settled, Yvorne, is located in the Rhone valley upstream from Lake Geneva about an hour's drive from his birth place. His residence became known as the Ant Hill. He devoted his time completely to the study of ants until his death at age 84, though he remained passionate about the curse of alcoholism and other human causes.

The locals remember him as an oddball ant lover who walked through their vineyards ranting and raving about their drinking habits. Obviously, the condemnation of wine consumption was at odds with the vintners' idea of their pleasurable products for refined tastes that constituted their livelihoods. Otherwise, they got along fine. Alas, the most prominent inhabitant of the village did not affect life in the village one single bit. Now as then, the smell of freshly pressed grapes permeates the air every September.

Moreover, Forel never managed to become truly accepted by the academic establishment of his francophonic homeland. He had to go through great troubles to obtain a medical license for this region and was never offered an academic appointment, regardless of his extraordinary scientific achievements and international acclaim. Only the burghers of Lausanne and Geneva know the reasons. Jean Calvin's ideals loom large there. Perhaps, Forel was too famous for them. By contrast, on the national level Auguste-Henri Forel was held in highest esteem. He was honored with a portrait on the largest denomination of the Swiss currency worth approximately $1,000.-. The banknote was in circulation until the year 2000. It was withdrawn because of counterfeiting. Its backside featured engravings of a neuron and an ant. I do not know of any other banknote dedicated to the brain and behavioral sciences.

I learned about Forel's research when I was working at the Institute of Anatomy of the University of Lausanne medical school. My colleagues and I were studying the influence of sensory input on brain development. I used the mouse somatic sensory system as a model. I already described the peculiarities of this system in my post dated May 15, 2008. The whiskers on the mouse's snout are represented topographically in the cerebral cortex of the brain by cytoarchitectonic units called barrels. The fifth cranial nerve, also known as the trigeminal nerve, innervates the face. Sensory trigeminal nerve fibers connect the pressure-sensitive receptor cells in the whisker follicles to the trigeminal sensory brainstem. From the brainstem the pathway crosses over to the other side and the input is relayed via the somatic sensory thalamus to the appropriate barrels in a one whisker-to-one barrel fashion.

Barrels develop in the first week after birth. When whisker follicles are removed at birth the corresponding barrels do not develop and the neighboring barrels enlarge. The critical period in which the barrels are plastic ceases once they are formed. The topographic order of the whisker input to somatic sensory cortex and its plasticity make the mouse whisker-to-barrel pathway a particularly useful model to examine the instructive power of sensory input on the development of sensory representation in the brain.

I set out to compare functional whisker representations in somatic sensory cortex, that is the areas whisker deflection activates in metabolic imaging, with the barrels. The follicles of select whiskers were removed in the critical period of brain development and in maturity. Early in his career, Auguste Forel conducted experiments, the results of which were instrumental to the hypotheses in my research.

The pictures above show a view of Yvorne (top, left), Forel at work in the Ant Hill (top, right), microscopic drawings of sections through the brainstem stained for nerve cells and fibers (bottom, left), and his description of the findings (bottom, right). He had examined in rabbits the consequences of cutting the trigeminal nerve at the root where it enters the brain. The microscopic drawings above show the nerve cells receiving the sensory trigeminal input (pink) and bundles of incoming trigeminal nerve fibers (brown) in the brainstem with an unperturbed trigeminal nerve (left) and after a nerve cut (right). Forel was probably the first to document a glial reaction to injury in the nervous system. Glia are types of brain cells distinct from nerve cells. They provide maintenance and support the immune response in the brain. I have written about this discovery in my post dated Dec. 16, 2007.

Important to his theory of the neuron, Forel noted that the incoming nerve fibers considerably diminished in number after the cut, whereas the density of nerve cells appeared increased. Careful, subsequent analysis showed that the increase in density resulted from tissue shrinkage. The number of nerve cells actually remained unchanged. This finding suggested that the cells of the nervous system were not fused into a continuous web as some scientists believed at the time. By contrast, the cells constituted independent members of an indirectly-connected network. In this network, no single member needed to show all functional attributes of the whole inasmuch as the behavior of a single ant does not reveal the destiny of the colony. The Gestalt psychologists would pick up on this idea and propose that in matters of brain and mind the whole was more than the mere sum of the pieces. I wrote about this school of thought in my post dated June 6, 2008. The cellular structure that permits communication between nerve cells without fusion is known as synapse today and was discovered only with the advent of the electron microscope half a century later.

The cell bodies of the trigeminal nerve fibers lie between the nerve's root at the brain and the nerve's endings in the skin. Forel cut the nerve at the root resulting in the degeneration of the projections that innervate the brainstem of the central nervous system. The severed central projections do not regenerate. By contrast, the removal of whisker follicles in my studies disrupted the peripheral trigeminal sensory projections innervating the mouse's face. Peripherally projecting nerve fibers regrow vigorously and attempt to find targets in the skin, particularly in the mature nervous system. Properly guided, they are able to restore functional innervation. I experienced the potential of restoration myself in two instances with opposite outcomes.

In addition to the face's skin, the trigeminal nerve innervates our teeth. At one time, I had to undergo orthodontic surgery to treat an inflammation in a root canal. During the procedure the branch of the trigeminal nerve that innervates the lower jaw and lower lip was crushed. My cheek and half of the lip remained numb after the anesthesia had worn off. But within six weeks, sensation returned successively, progressing toward the tip of the lip. I still vividly recall the moment when the numbness on the lip vanished with a slight tingling sensation and my sense of touch was completely restored. Apparently, the regenerating nerve fibers had successfully found their targets.

I was less fortunate on another occasion. I accidentally cut myself deep in the palmar surface of the right index finger, partially severing its sensory innervation. The accident happened 30 years ago. Half of my finger remains numb today. I have to be careful when I open bottles with twist caps, because I do not feel the pain before it is too late. Obviously, the regrowing nerve fibers were not able to bridge the injury and re-innervate the skin. They lacked the guide of the sheeth wrapping the nerve. The nerve stumps had become separated and misaligned in the accident. Today, surgeons are careful to reconnect nerve sheeths in reconstructive procedures to ensure optimal restoration of innervation.

Forel's insights into the relationships between ants and nerve cells spawned a number of hypotheses in my work about possible nerve cell responses to the loss of sensory input. I imagined the ensemble of nerve cells interacting in the brain in analogy to an orchestra of ants, the Orchestre de Mille Francs, OMF for short. The members of the OMF grow up and learn to play music together. Each member must play their instrument in context of the music the other members play. Though the members are independent players, they need to listen to one another and coordinate their actions in order to perform in meaningful symphony. What would happen if members break their instrument? What would happen if they break a limb? Can the remaining members substitute? Does it depend on the kind of instrument the member was playing? Would the music change? Could the melody be restored? Did the changes depend on the proficiency of the players? Was the potential for change greater with beginners than with seasoned virtuosos? The drawings shown below helped flesh out possible scenarios.

L'orchestre de mille Francs

One intriguing finding of my mouse studies was that the functional cortical representations of the intact whiskers adjacent to the removed ones enlarged into the territory left vacant by the removal. The functional whisker representations were modified even when whisker follicles were removed in adult mice long after the critical period for barrels had ended. This plasticity of functional sensory representation may provide a basis for the perception of a continuous tactile field while the sensory nerve fibers in the facial skin reorganize. The regeneration of peripheral innervation is particularly strong when the nervous system is mature. My studies and the studies of others showed that whisker follicles remaining in the skin attract the newly regenerated nerve fibers and are innervated by them within three months. The findings suggest that it may be worthwhile to surgically provide guides for regrowing nerve endings months after the disruption of innervation. An extended program of exercises providing continued sensory stimulation may help boost new functionality.


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